Many articles or products are very sensitive to heat exposure, such as most of vaccines (usually stored and transported between 2° C. and 8° C.), biological products, bioactive samples and some drugs and the like, as well as fresh foods such as fresh milk, dairy product, fresh meat, fresh fish and the like, need to be stored or transported at low temperature. For long time, the main methods for ensuring the safe use of these articles/products, especially drugs or foods, comprise labeling the valid period, the quality guarantee period or the fresh preservation period. However, these methods usually can not tell whether those drugs or foods which need to be stored and transported at low temperature have been exposed at a temperature exceeding the safe storage and transport conditions for too long time, and thus to excessive heat. The safety and efficacy of various thermosensitive articles can be better ensured by using a simple and inexpensive method to accurately indicate whether the thermosensitive articles, such as fresh food, vaccines, bioactive samples and the like which need to be stored at low temperature, deteriorate, fail or lose activity due to excessive heat exposure.
In the 1990s, the World Health Organization (WHO) began to pay attention to the problem that vaccines are exposed to heat during the cold chain storage and transport, because this will lead to a decrease in the immune effect of the vaccines, thereby reducing the protection of vaccines for children. Subsequently, the WHO called for the development of a label which is easy to use and inexpensive so as to accurately reflect the heat history of vaccines from leaving the factory after manufacture, being transported and stored, to reaching end users. The essential requirements for the label are shown as follows: 1. it can accurately indicate the vaccine exposed to excessive heat and thus restrict the use thereof; 2. it has a small volume, and can be adhered to a vaccine bottle, an ampoule, an injector or the like; 3. it is stable and reliable during the whole process from production to actual use; and 4. it is suitable for mass production in low cost and meets the global demand for vaccines of United Nations International Children's Emergency Fund (UNICEF).
In 1996, the TempTime company (formerly known as Lifelines) in USA developed a label which can meet the requirements of WHO for the first time. The label is applied to the polio vaccines produced by three vaccine manufacturers, i.e., GlaxoSmithKline, Sanofi-Pasteur and Novartis. The labels provided by Temptime are classified into three categories according to the functions thereof. The first type is Critical Temperature Indicator (CTI), which immediately changes colour once the temperature exceeds a set value. The second one is Critical Temperature-Time Indicator (CTTI), the colour change of which delays to some extent, that is, the label changes colour after exposing to a temperature above the set value for several minutes or tens of minutes. The third one is known as Time-Temperature Indicator (TTI), which has a longer response time, and in which the temperature sensing material changes colour after receiving a certain amount of heat. This kind of label is a label suitable for indicating the heat history of vaccines.
Currently, there are hundreds of patents related to such thermosensitive labels in the world. These patented technologies can be classified into mechanical type, chemical type, enzyme reaction type, microorganism type, polymer type, electronic type, diffusion type and the like according to the operating principles of the products. These technologies are mainly based on mechanical property, electrical property, diffusion property, bio-enzyme reaction, polymerization and the like of the functional materials. There are mainly three kinds of TTI labels which are well established and already commercialized: polymer type, enzyme reaction type and diffusion type.
The polymer type label is developed by TempTime company in USA, and is based on the formation of a coloured polymer as a result of solid state 1,4-addition polymerization of a substituted diacetylene derivative. The rate of polymerization increases as the temperature rises. The continuously formed polymer makes the colour darker continuously, which, by comparison with the surrounding colour, indicates whether the vaccines have been exposed to excessive heat. It is required to screen and synthesize suitable polymeric monomer for such a label. Further, the label needs to be stored at the temperature of −18° C. or even lower after its production, which obviously increases the cost of use of the label.
An early indicator of enzyme reaction type is essentially a kind of pH indicator, which indicates the heat history by measuring the colour change caused by the pH value change of the medium which is caused by the protons H+ released from the enzyme-catalyzed hydrolysis of lipids substrate. The enzymatic hydrolysis becomes faster as the temperature rises, and thus the release rate of protons also becomes faster. A typical one is Vitsab ring indicator developed by a Swedish company.
An earlier typical product of diffusion type label is the 3M Monitor Mark indicator produced by 3M company in USA, based on the diffusion of a dye on a string, in which the temperature indicating range and response time depend on the type of dyes. Another form of diffusion type indicator can be prepared by coating a porous substrate with a material having a specific melting point. The optical refractive indexes of the substrate and the material are close to each other. When the coating material melts at above a specific temperature and diffuses into the porous substrate so that the air in the pores of the substrate is exhausted, the transmittance of the substrate increases, and thus a colour change can be achieved, showing the accumulated heat exposure.
Currently, WHO classifies about twenty vaccines into 4 categories based on their thermal stability: the most unstable vaccines, unstable vaccines, stable vaccines and highly stable vaccines, and thus proposes the technical requirements for corresponding thermosensitive labels. The technical standards thus established take the properties of indicator products in the prior art into account, but are not based on the thermal stability of vaccines per se completely. In fact, since each of the about twenty vaccines which need cold chain storage and transport and to be monitored during the whole process has different thermal stability, an ideal thermosensitive label should be an individualized thermosensitive label adequately reflecting the thermal stability of the product indicated, i.e. the rate of colour change and the temperature effect thereof should keep as consistent as possible with the failure process of the indicated product.
Therefore, in the art there is still a need for a thermosensitive label and a method for monitoring the heat history of a thermosensitive article, in order to monitor the storage and transport of a thermosensitive article conveniently, and accurately indicate whether a thermosensitive article fails or deteriorates. Particularly, the thermosensitive label per se can be stored at room temperature before use.